Endothelial deficiency of insulin-like growth factor-1 receptor leads to blood-brain barrier disruption and accelerated endothelial senescence in mice, mimicking aspects of the brain aging phenotype.

INTRODUCTION: Age-related blood-brain barrier (BBB) disruption, cerebromicrovascular senescence, and microvascular rarefaction substantially contribute to the pathogenesis of vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Previous studies established a causal link between age-related decline in circulating levels of insulin-like growth factor-1 (IGF-1), cerebromicrovascular dysfunction, and cognitive decline. The aim of our study was to determine the effect of IGF-1 signaling on senescence, BBB permeability, and vascular density in middle-age and old brains. METHODS: Accelerated endothelial senescence was assessed in senescence reporter mice (VE-Cadherin-CreERT2 /Igf1rfl/fl × p16-3MR) using flow cytometry. To determine the functional consequences of impaired IGF-1 input to cerebromicrovascular endothelial cells, BBB integrity and capillary density were studied in mice with endothelium-specific knockout of IGF1R (VE-Cadherin-CreERT2 /Igf1rfl/fl ) using intravital two-photon microscopy. RESULTS: In VE-Cadherin-CreERT2 /Igf1rfl/fl mice: (1) there was an increased presence of senescent endothelial cells; (2) cumulative permeability of the microvessels to fluorescent tracers of different molecular weights (0.3-40 kDa) is significantly increased, as compared to that of control mice, whereas decline in cortical capillary density does not reach statistical significance. CONCLUSIONS: These findings support the notion that IGF-1 signaling plays a crucial role in preserving a youthful cerebromicrovascular endothelial phenotype and maintaining the integrity of the BBB.

Tetraspanin Tspan8 restrains interferon signaling to stabilize intestinal epithelium by directing endocytosis of interferon receptor.

Inflammation can impair intestinal barrier, while increased epithelial permeability can lead to inflammation. In this study, we found that the expression of Tspan8, a tetraspanin expressed specifically in epithelial cells, is downregulated in mouse model of ulcerative disease (UC) but correlated with those of cell-cell junction components, such as claudins and E-cadherin, suggesting that Tspan8 supports intestinal epithelial barrier. Tspan8 removal increases intestinal epithelial permeability and upregulates IFN-γ-Stat1 signaling. We also demonstrated that Tspan8 coalesces with lipid rafts and facilitates IFNγ-R1 localization at or near lipid rafts. As IFN-γ induces its receptor undergoing clathrin- or lipid raft-dependent endocytosis and IFN-γR endocytosis plays an important role in Jak-Stat1 signaling, our analysis on IFN-γR endocytosis revealed that Tspan8 silencing impairs lipid raft-mediated but promotes clathrin-mediated endocytosis of IFN-γR1, leading to increased Stat1 signaling. These changes in IFN-γR1 endocytosis upon Tspan8 silencing correlates with fewer lipid raft component GM1 at the cell surface and more clathrin heavy chain in the cells. Our findings indicate that Tspan8 determines the IFN-γR1 endocytosis route, to restrain Stat1 signaling, stabilize intestine epithelium, and subsequently prevent intestine from inflammation. Our finding also implies that Tspan8 is needed for proper endocytosis through lipid rafts.

Neurovascular coupling, functional connectivity, and cerebrovascular endothelial extracellular vesicles as biomarkers of mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.

NO Deficiency Compromises Inter- and Intrahemispheric Blood Flow Adaptation to Unilateral Carotid Artery Occlusion.

Carotid artery stenosis (CAS) affects approximately 5-7.5% of older adults and is recognized as a significant risk factor for vascular cognitive impairment (VCI). The impact of CAS on cerebral blood flow (CBF) within the ipsilateral hemisphere relies on the adaptive capabilities of the cerebral microcirculation. In this study, we aimed to test the hypothesis that the impaired availability of nitric oxide (NO) compromises CBF homeostasis after unilateral carotid artery occlusion (CAO). To investigate this, three mouse models exhibiting compromised production of NO were tested: NOS1 knockout, NOS1/3 double knockout, and mice treated with the NO synthesis inhibitor L-NAME. Regional CBF changes following CAO were evaluated using laser-speckle contrast imaging (LSCI). Our findings demonstrated that NOS1 knockout, NOS1/3 double knockout, and L-NAME-treated mice exhibited impaired CBF adaptation to CAO. Furthermore, genetic deficiency of one or two NO synthase isoforms increased the tortuosity of pial collaterals connecting the frontoparietal and temporal regions. In conclusion, our study highlights the significant contribution of NO production to the functional adaptation of cerebrocortical microcirculation to unilateral CAO. We propose that impaired bioavailability of NO contributes to the impaired CBF homeostasis by altering inter- and intrahemispheric blood flow redistribution after unilateral disruption of carotid artery flow.

Microvascular dysfunction and neurovascular uncoupling are exacerbated in peripheral artery disease, increasing the risk of cognitive decline in older adults.

Peripheral artery disease (PAD) is a vascular pathology with high prevalence among the aging population. PAD is associated with decreased cognitive performance, but the underlying mechanisms remain obscure. Normal brain function critically depends on an adequate adjustment of cerebral blood supply to match the needs of active brain regions via neurovascular coupling (NVC). NVC responses depend on healthy microvascular endothelial function. PAD is associated with significant endothelial dysfunction in peripheral arteries, but its effect on NVC responses has not been investigated. This study was designed to test the hypothesis that NVC and peripheral microvascular endothelial function are impaired in PAD. We enrolled 11 symptomatic patients with PAD and 11 age- and sex-matched controls. Participants were evaluated for cognitive performance using the Cambridge Neuropsychological Test Automated Battery and functional near-infrared spectroscopy to assess NVC responses during the cognitive n-back task. Peripheral microvascular endothelial function was evaluated using laser speckle contrast imaging. We found that cognitive performance was compromised in patients with PAD, evidenced by reduced visual memory, short-term memory, and sustained attention. We found that NVC responses and peripheral microvascular endothelial function were significantly impaired in patients with PAD. A positive correlation was observed between microvascular endothelial function, NVC responses, and cognitive performance in the study participants. Our findings support the concept that microvascular endothelial dysfunction and neurovascular uncoupling contribute to the genesis of cognitive impairment in older PAD patients with claudication. Longitudinal studies are warranted to test whether the targeted improvement of NVC responses can prevent or delay the onset of PAD-associated cognitive decline.NEW & NOTEWORTHY Peripheral artery disease (PAD) was associated with significantly decreased cognitive performance, impaired neurovascular coupling (NVC) responses in the prefrontal cortex (PFC), left and right dorsolateral prefrontal cortices (LDLPFC and RDLPFC), and impaired peripheral microvascular endothelial function. A positive correlation between microvascular endothelial function, NVC responses, and cognitive performance may suggest that PAD-related cognitive decrement is mechanistically linked, at least in part, to generalized microvascular endothelial dysfunction and subsequent impairment of NVC responses.

A Central Role for TRPM4 in Ca2+-Signal Amplification and Vasoconstriction.

Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca2+ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca2+ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca2+ concentration, suggesting an inhibition of Ca2+ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca2+ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca2+-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca2+ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site.

Obesity-induced cognitive impairment in older adults: a microvascular perspective.

Over two-thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction, and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.

Demonstration of age-related blood-brain barrier disruption and cerebromicrovascular rarefaction in mice by longitudinal intravital two-photon microscopy and optical coherence tomography.

Age-related blood-brain barrier (BBB) disruption and cerebromicrovascular rarefaction contribute importantly to the pathogenesis of both vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). Recent advances in geroscience research enable development of novel interventions to reverse age-related alterations of the cerebral microcirculation for prevention of VCID and AD. To facilitate this research, there is an urgent need for sensitive and easy-to-adapt imaging methods that enable longitudinal assessment of changes in BBB permeability and brain capillarization in aged mice and that could be used in vivo to evaluate treatment efficiency. To enable longitudinal assessment of changes in BBB permeability in aged mice equipped with a chronic cranial window, we adapted and optimized two different intravital two-photon imaging approaches. By assessing relative fluorescence changes over the baseline within a volume of brain tissue, after qualitative image subtraction of the brain microvasculature, we confirmed that, in 24-mo-old C57BL/6J mice, cumulative permeability of the microvessels to fluorescent tracers of different molecular masses (0.3 to 40 kDa) is significantly increased compared with that of 5-mo-old mice. Real-time recording of vessel cross-sections showed that apparent solute permeability of single microvessels is significantly increased in aged mice vs. young mice. Cortical capillary density, assessed both by intravital two-photon microscopy and optical coherence tomography was also decreased in aged mice vs. young mice. The presented methods have been optimized for longitudinal (over the period of 36 wk) in vivo assessment of cerebromicrovascular health in preclinical geroscience research.NEW & NOTEWORTHY Methods are presented for longitudinal detection of age-related increase in blood-brain barrier permeability and microvascular rarefaction in the mouse cerebral cortex by intravital two-photon microscopy and optical coherence tomography.

Mechanisms of Vascular Aging.

Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.

Prostaglandin E2, a postulated mediator of neurovascular coupling, at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles.

There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance-sized human cerebral parenchymal arterioles. To achieve this goal PGE2-induced isotonic vasomotor responses were assessed in parenchymal arterioles isolated from fronto-temporo-parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined. In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10-8 to 10-6 mol/l) caused significant, endothelium-independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1-dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA and protein expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human patients.

Disruption of Interneuron Neurogenesis in Premature Newborns and Reversal with Estrogen Treatment.

Many Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and that restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we compared interneuronal progenitors in the medial ganglionic eminences (MGEs), lateral ganglionic eminences (LGEs), and caudal ganglionic eminences (CGEs) between preterm-born [born on embryonic day (E) 29; examined on postnatal day (D) 3 and D7] and term-born (born on E32; examined on D0 and D4) rabbits at equivalent postconceptional ages. We found that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGEs of preterm rabbits at D3 compared with term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGEs of preterm pups at D3 compared with term rabbits at D0. Dlx2+ cells in CGEs were comparable between preterm and term pups. Simulation of hypoxia by dimethyloxalylglycine treatment did not affect the number of interneuronal progenitors. However, estrogen treatment reduced the density of total and proliferating Nkx2.1+ and Dlx2+ cells in the MGEs and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting inhibition of the G1-to-S phase transition. Hence, preterm birth disrupts interneuron neurogenesis in the MGE and estrogen treatment reverses interneuron neurogenesis in preterm newborns by cell-cycle inhibition and elevation of Ascl1. We speculate that estrogen replacement might partially restore neurogenesis in human premature infants.SIGNIFICANCE STATEMENT Prematurity results in developmental delays and neurobehavioral disorders, which might be ascribed to disturbances in the development of cortical interneurons. Here, we show that preterm birth disrupts interneuron neurogenesis in the medial ganglionic eminence (MGE) and, more importantly, that estrogen treatment reverses this perturbation in the population of interneuron progenitors in the MGE. The estrogen seems to restore neurogenesis by inhibiting the cell cycle and elevating Ascl1 expression. As preterm birth causes plasma estrogen level to drop 100-fold, the estrogen replacement in preterm infants is physiological. We speculate that estrogen replacement might ameliorate disruption in production of interneurons in human premature infants.

Role of endothelial NAD+ deficiency in age-related vascular dysfunction.

Age-related alterations in endothelium and the resulting vascular dysfunction critically contribute to a range of pathological conditions associated with old age. To develop therapies rationally that improve vascular health and thereby increase health span and life span in older adults, it will be essential to understand the cellular and molecular mechanisms contributing to vascular aging. Preclinical studies in model organisms demonstrate that NAD+ availability decreases with age in multiple tissues and that supplemental NAD+ precursors can ameliorate many age-related cellular impairments. Here, we provide a comprehensive overview of NAD+-dependent pathways [including the NAD+-using silent information regulator-2-like enzymes and poly(ADP-ribose) polymerase enzymes] and the potential consequences of endothelial NAD+ deficiency in vascular aging. The multifaceted vasoprotective effects of treatments that reverse the age-related decline in cellular NAD+ levels, as well as their potential limitations, are discussed. The preventive and therapeutic potential of NAD+ intermediates as effective, clinically relevant interventions in older adults at risk for ischemic heart disease, vascular cognitive impairment, and other common geriatric conditions and diseases that involve vascular pathologies (e.g., sarcopenia, frailty) are critically discussed. We propose that NAD+ precursors [e.g., nicotinamide (Nam) riboside, Nam mononucleotide, niacin] should be considered as critical components of combination therapies to slow the vascular aging process and increase cardiovascular health span.

Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment.

There has been an increasing appreciation of the role of vascular contributions to cognitive impairment and dementia (VCID) associated with old age. Strong preclinical and translational evidence links age-related dysfunction and structural alterations of the cerebral arteries, arterioles, and capillaries to the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. The low-pressure, low-velocity, and large-volume venous circulation of the brain also plays critical roles in the maintenance of homeostasis in the central nervous system. Despite its physiological importance, the role of age-related alterations of the brain venous circulation in the pathogenesis of vascular cognitive impairment and dementia is much less understood. This overview discusses the role of cerebral veins in the pathogenesis of VCID. Pathophysiological consequences of age-related dysregulation of the cerebral venous circulation are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages of venous origin, altered production of cerebrospinal fluid, impaired function of the glymphatics system, dysregulation of cerebral blood flow, and ischemic neuronal dysfunction and damage. Understanding the age-related functional and phenotypic alterations of the cerebral venous circulation is critical for developing new preventive, diagnostic, and therapeutic approaches to preserve brain health in older individuals.

Single Mild Traumatic Brain Injury Induces Persistent Disruption of the Blood-Brain Barrier, Neuroinflammation and Cognitive Decline in Hypertensive Rats.

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1ß and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Glycogen synthase kinase-3ß inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A.

Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3ß inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These hypotheses were tested in autopsy samples from preterm infants and in a rabbit model of IVH. Induction of IVH reduced expressions of activated ß-catenin, TCF-4, and Axin2 transcription factors in preterm newborns. Both AR-A014418 (ARA) and Wnt-3A treatment activated Wnt signaling. GSK-3ß inhibition by intramuscular ARA treatment accelerated maturation of OPCs, myelination, and neurological recovery in preterm rabbits with IVH compared to vehicle controls. In contrast, intracerebroventricular rh-Wnt3A treatment failed to enhance myelination and neurological function in rabbits with IVH. ARA treatment reduced microglia infiltration and IL1ß expression in rabbits with IVH relative to controls, whereas Wnt3A treatment elevated TNFα, IL1ß, and IL6 expression without affecting microglia density. GSK-3ß inhibition downregulated, while rh-Wnt3A treatment upregulated Notch signaling; and none of the two treatments affected the Sonic-Hedgehog pathway. The administration of ARA or rh-Wnt3A did not affect gliosis. The data suggest that GSK-3ß inhibition promoted myelination by suppressing inflammation and Notch signaling; and Wnt3A treatment failed to enhance myelination because of its pro-inflammatory activity and synergy with Notch signaling. GSK-3ß inhibitors might improve the neurological outcome of preterm infants with IVH.

Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment.

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer's disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR-/-) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR-/- mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.

Pharmacological Strategies to Retard Cardiovascular Aging.

Aging is the major risk factor for cardiovascular diseases, which are the leading cause of death in the United States. Traditionally, the effort to prevent cardiovascular disease has been focused on addressing the conventional risk factors, including hypertension, hyperglycemia, hypercholesterolemia, and high circulating levels of triglycerides. However, recent preclinical studies have identified new approaches to combat cardiovascular disease. Calorie restriction has been reproducibly shown to prolong lifespan in various experimental model animals. This has led to the development of calorie restriction mimetics and other pharmacological interventions capable to delay age-related diseases. In this review, we will address the mechanistic effects of aging per se on the cardiovascular system and focus on the prolongevity benefits of various therapeutic strategies that support cardiovascular health.

AMPA-Kainate Receptor Inhibition Promotes Neurologic Recovery in Premature Rabbits with Intraventricular Hemorrhage.

Intraventricular hemorrhage (IVH) in preterm infants leads to cerebral inflammation, reduced myelination of the white matter, and neurological deficits. No therapeutic strategy exists against the IVH-induced white matter injury. AMPA-kainate receptor induced excitotoxicity contributes to oligodendrocyte precursor cell (OPC) damage and hypomyelination in both neonatal and adult models of brain injury. Here, we hypothesized that IVH damages white matter via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and restores OPC maturation, myelination, and neurologic recovery in preterm newborns with IVH. We tested these hypotheses in a rabbit model of glycerol-induced IVH and evaluated the expression of AMPA receptors in autopsy samples from human preterm infants. GluR1-GluR4 expressions were comparable between preterm humans and rabbits with and without IVH. However, GluR1 and GluR2 levels were significantly lower in the embryonic white matter and germinal matrix relative to the neocortex in both infants with and without IVH. Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA receptor inhibition by intramuscular perampanel restored myelination and neurologic recovery in rabbits with IVH. NBQX administration also reduced the population of apoptotic OPCs, levels of several cytokines (TNFα, IL-ß, IL-6, LIF), and the density of Iba1(+) microglia in pups with IVH. Additionally, NBQX treatment inhibited STAT-3 phosphorylation, but not astrogliosis or transcription factors regulating gliosis. Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-induced inflammation and restores myelination and neurologic recovery in preterm rabbits with IVH. Therapeutic use of FDA-approved perampanel treatment might enhance neurologic outcome in premature infants with IVH. SIGNIFICANCE STATEMENT: Intraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH.

Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging.

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) are expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function, and neurovascular coupling responses responsible for functional hyperemia. The pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction, and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID has captured in recent years, the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined.

Cerebral microhemorrhages: mechanisms, consequences, and prevention.

The increasing prevalence of multifocal cerebral microhemorrhages (CMHs, also known as "cerebral microbleeds") is a significant, newly recognized problem in the aging population of the Western world. CMHs are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function, potentially contributing to cognitive decline, geriatric psychiatric syndromes, and gait disorders. Clinical studies show that aging and hypertension significantly increase prevalence of CMHs. CMHs are also now recognized by the National Institutes of Health as a major factor in Alzheimer's disease pathology. Moreover, the presence of CMHs is an independent risk factor for subsequent larger intracerebral hemorrhages. In this article, we review the epidemiology, detection, risk factors, clinical significance, and pathogenesis of CMHs. The potential age-related cellular mechanisms underlying the development of CMHs are discussed, with a focus on the structural determinants of microvascular fragility, age-related alterations in cerebrovascular adaptation to hypertension, the role of oxidative stress and matrix metalloproteinase activation, and the deleterious effects of arterial stiffening, increased pulse pressure, and impaired myogenic autoregulatory protection on the brain microvasculature. Finally, we examine potential treatments for the prevention of CMHs based on the proposed model of aging- and hypertension-dependent activation of the reactive oxygen species-matrix metalloproteinases axis, and we discuss critical questions to be addressed by future studies.